BR112013018527B1 - ANALGESIC COMPOUNDS, AND PHARMACEUTICAL FORMULATION - Google Patents

Abstract

analgesic compounds and pharmaceutical formulation. The present invention relates to analgesic compounds and salts thereof, of formula I: in which pharmaceutical formulations employing the above compounds are provided.

Description

[001] Opiates, a class of centrally acting compounds, are the most frequently employed agents to alleviate and control pain, and which act on one or more of the human or mammalian opiate receptors. Technically, opiates are the natural alkaloids found in the resin of the opium poppy, but current usage of the term includes synthetic variations, called opioids. Opiates are narcotic agonistic analgesics and are drugs including or derivatives of opium, such as morpholine, codeine, and many synthetic congeners of morpholine, with morpholine and hydrocodone preparations being the most widely used opiates. Opiates are synthetic, natural drugs with actions like morpholine, and are subject to control under the US Federal Narcotics Act (intended drugs) and laws and most other nations and international organizations because of their addictive properties and the subsequent exact destructive toll on abusers and those with any connection to them.

[002] Tramadol is a synthetic analogue of the phenanthrene alkaloid codeine and as such is an opioid as well as a prodrug (codeine is metabolized to morpholine, tramadol is converted to M1 also called O-desmethyltramadol). Tramadol, like opiates, is associated with adverse effects such as physical and psychological dependence, severe withdrawal symptoms, as well as other slightly less serious side effects, including nausea, vomiting, sweating, constipation and drowsiness.

[003] While opiates and related drugs clearly serve useful purposes, alternative therapies and compounds for pain relief are desirable due to the known problems of opiates. Particularly, compounds which are unintended, take into account the lower dosing frequency, and/or do not exhibit side effects at all or to the degree associated with the opiates and related drugs, would provide such alternative therapies.

[004] WO2002/26694 refers to O-substituted 6-methyl-tramadol derivatives, processes for their production, medicines containing the derivatives and uses of derivatives to treat pain.

[005] EP112787 refers to novel esters derived from substituted phenyl-cyclohexyl compounds, which are derived from tramadol.

[006] WO2003/048113 refers to tramadol analogues useful for the treatment of CNS related disorders including pain, anxiety, depression and attention deficit disorder.

[007] EP2022778 refers to a (R,R)-tramadol-(S)-naproxen salt, a crystalline form of (R,R)-tramadol-(S)-naproxen salt and its processes for preparation and use as a medicine for the treatment of pain.

[008] GB997399 refers to phenol ethers that contain basic groups and the methods for preparing them.

[009] US3564100 refers to cycloalkene compounds and processes for their preparation.

[010] US3652589 refers to phenol ethers substituted by cycloalkanol having basic groups, pharmaceutical compositions containing the compounds, processes for preparing the compounds and methods of employing the compounds.

[011] Atzneimittel-Forschung/Drug Research, Vol. 28, No. 1a (1978) pages 107-113 refers to phenyl substituted aminomethylcycloalkanol compounds tested for analgesic properties.

[012] Journal of the Mexican Chemical Society, Vol. 49, No. 4, (2005) pages 324-327 refers to tramadol and tramadol derivatives, and the processes for preparing them.

na qual

R1 é hidrogênio, C1-C5 alquila, C1-C5 alcóxi, C1-C5 haloal- quila, C1-C5 alcanol, -(C1-C5 alquil)fenila, ou fenila, ou um grupo da Fórmula -C(O)-R12, onde R12pode ser C1-C5 alquila, C1-C5 alcóxi, Ci- C5 haloalquila, C1-C5 alcanol, -(C1-C5 alquil)fenila, ou fenila; R2é hidrogênio, C1-C5 alquila, C1-C5 alcóxi, halogênio, C1-C5haloalquila, ou C1-C5 haloalcóxi; R3é hidrogênio, C1-C5 alquila, C1-C5 alcóxi, halogênio, C1-C5haloalquila, ou C1-C5 haloalcóxi; R4é hidrogênio, C1-C5 alquila, ou -(C1-C5 alquil)fenila; R5é hidrogênio, C1-C5 alquila, ou -(C1-C5 alquil)fenila; R6é hidrogênio, hidróxi, ou é ausente; R7é hidrogênio; R8é hidrogênio ou metila; R9é hidrogênio ou metila; R10é hidrogênio; R11é hidrogênio ou C1-C5 alquila; ou R7e R10combinam para formar -CH2- ou -(CH2)2-; ou R8e R9combinam para formar um grupo ciclopropila com o carbon ao qual eles são ligados; ou R10e R11 combinam para formar -CH2- ou -(CH2)3- .[013] Provided are the analgesic compounds and salts thereof, of Formula I:

in which

R1 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C1-C5 alkanol, -(C1-C5 alkyl)phenyl, or phenyl, or a group of the Formula -C(O)-R12 , where R 12 may be C 1 -C 5 alkyl, C 1 -C 5 alkoxy, C 1 -C 5 haloalkyl, C 1 -C 5 alkanol, -(C 1 -C 5 alkyl)phenyl, or phenyl; R2is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, C1-C5haloalkyl, or C1-C5 haloalkoxy; R3is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, C1-C5haloalkyl, or C1-C5 haloalkoxy; R4is hydrogen, C1-C5 alkyl, or -(C1-C5 alkyl)phenyl; R5is hydrogen, C1-C5 alkyl, or -(C1-C5 alkyl)phenyl; R6 is hydrogen, hydroxy, or is absent; R7is hydrogen; R8 is hydrogen or methyl; R9 is hydrogen or methyl; R10 is hydrogen; R11 is hydrogen or C1-C5 alkyl; or R7and R10combine to form -CH2- or -(CH2)2-; or R8and R9combine to form a cyclopropyl group with the carbon to which they are attached; or R10and R11 combine to form -CH2- or -(CH2)3-.

[014] More particularly, A can be:

[015] Of the first four definitions immediately above for A, the following are preferred:

[016] C1-C5 alkyl refers to straight or branched chain alkyls having one to five carbon atoms, and includes methyl, ethyl, propyl, n-butyl, iso-butyl, pentyl, isopentyl, and neopentyl.

[017] C1-C5 alkoxy refers to straight or branched chain alkoxys having one to five carbon atoms, and includes methoxy, ethoxy, propoxy, n-butoxy, iso-butoxy, pentoxy, isopentoxy, and neopentoxy.

[018] Halogen or halo refers to fluorine, bromine, chlorine, and iodine.

[019] Haloalkyl as used herein refers to an alkyl (as mentioned above) substituted with one or more halo atoms. Such groups include trifluoromethyl, methylchloride, dichloromethyl, pentylchloride, butyl chloride, and isopropyl chloride.

[020] Haloalkoxy refers to an alkoxy group, as described herein, which is substituted with one to six halo groups. Examples of fluoroalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, and trifluoroethoxy.

[021] C1-C5 alkanols refers to methanol, ethanol, propanol, or methoxyethanol.

como apropriado.[022] In the definition of A:

as appropriate.

[023] PivCl refers to pivaloyl chloride.

[024] Pain control refers to suppressing, inhibiting, ameliorating, reducing, or eliminating pain, its severity, and/or duration. As such, the invention is applicable to the relief of existing pain as well as the suppression or inhibition of pain that would otherwise result from an event causing imminent pain. The pain being relieved can be chronic or acute.

[025] Mammals include both human and non-human mammals. Non-human mammals include domestic animals such as farm animals and companion animals. Farm animals include vacuum cattle, camellids, pigs, sheep, goats and horses. Companion animals include dogs, rabbits, cats, and other pets owned and kept in association with humans as part of the human-animal bond.

[026] The effective amount refers to the amount of a compound of Formula I, or a salt thereof, sufficient to control or alleviate pain in a mammal in need thereof, and as such will depend on a number of factors. Variations for a compound of Formula I, or a salt thereof, in the methods include from 0.01 to 1000 mg/kg and more desirably from 0.1 to 100 mg/kg of the animal's body weight. The frequency of administration will also be dependent on a number of factors, and may be a single dose administered once a day or once a week for a duration determined by the attending veterinarian or doctor. The dose may also be split into two or more smaller doses given over time to result in pain control or relief.

[027] Pharmaceutically acceptable as used in this application, for example, with reference to salts and formulation components such as vehicles, includes "veterinarily acceptable", and thus includes both human and animal applications independently.

[028] Pharmaceutically acceptable salts, and the common methodology for preparing them, are known in the art. See, for example, P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2002); S.M. Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977. A preferred salt is the hydrochloride salt.

[029] The compounds of Formula I and their salts can be formulated as pharmaceutical compositions for systemic administration. Such pharmaceutical compositions, and processes for preparing the same, are known in the art for both human and non-human mammals. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, (A. Gennaro, et al., eds., 19th ed., Mack Publishing Co., 1995). Additional active ingredients may be included in a formulation containing a compound of Formula I or a salt thereof.

[030] Vehicle is as used herein to describe any ingredient other than the active component(s) in a formulation. The choice of vehicle will depend on a wide range of factors such as the particular method of administration, the effect of the vehicle on solubility and stability, and the nature of the dosage form.

[031] The compounds of the invention can be prepared by the procedures described below, as well as the procedures described in Selnick, H.C.; Bourgeois, M.L.; Butcher, J.W.; Radzilowski, E.M. Tetrahedron Lett, 1993, 34, 2043; Alvarado, C; Guzmán, A.; Diaz, E.; Patino. R.J.Mex. Chem. Soc. 2005, 49, 324; Evans, G.R.; Palo-ma, Fernández, D.; Henshilwood, J.A., Lloyd, S.; Nicklin, C. Org. Process Res. Dev. 2002, 6, 729; and Mohacsi, E.; O'Brien, J.P.; Blount, J.F.J.Heterocycl.Chem. 1990, 27, 1623.

[032] The invention provides a pharmaceutical formulation comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical formulation may also comprise at least one additional active ingredient. A pharmaceutical formulation can be a human pharmaceutical formulation or a pharmaceutical-caveterinary formulation.

The invention provides a method of controlling pain in a mammal in need thereof comprising administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to said mammal. The method can also provide for administering at least one other active ingredient to said mammal. The mammal can be a human or non-human mammal, and it can also be a companion animal, such as a dog or cat.

[034] For compounds of Formula Ia, below, Schemes AC and Preparations and/or Examples 1-76 illustrate methods of preparing them.

[035] Stir a mixture of bicyclo[3.2.1]octan-3-one (5.2 g, 41.9 mmol), (HCHO)n (1.51 g, 50.3 mmol), dimethylamine hydrochloride ( 3.42 g, 41.9 mmol) and 0.5 mL conc. in MeCN (50 mL) at 80°C for 2 hours. After removing the solvent in vacuo, dissolve the residue in H2O (20 mL) and wash with EtOAc (20 mL x 3). Basify the aqueous solution with NaOH to pH = 10. Extract the resulting aqueous mixture with EtOAc (60 mL x 3). The combined organic layers are washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to remove crude 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one as brown oil (5.9 g, yield: 78.7%). MS (m/z): 182 (M+1). Example 2 Synthesis of 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol.

[036] Add dropwise a solution of t-BuLi (19.2 mL, 25.0 mmol) in hexane via syringe to a solution of 1-bromo-3-methoxy-benzene (3.74 g, 20.0 mmol) in THF (60 mL) at -78°C under N 2 . After being stirred at -78°C for 1 hour, add dropwise a solution of 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one (1.81 g, 10.0 mmol) in THF (10 mL) ) to the reaction mixture and stir the resulting mixture at -78°C for an additional 1 hour. Quench the reaction with saturated aqueous NH4Cl solution (20 mL). Extract the aqueous mixture with EtOAc (50 mL x 3). The combined organic layers are washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purify the residue by silica gel chromatography (CH2Cl2:MeOH = 30:1) to give 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol as white solid (1, 49 g, yield: 51%). MS (m/z): 290 (M+1).

Exemplo 14 Síntese de cloridrato de 2-dimetilaminometil-3-(3-metóxi-fenil)- biciclo[3.2.1] octan-3-ol.

[037] The following compounds can be prepared essentially by the method of Example 2.

Example 14 Synthesis of 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1] octan-3-ol hydrochloride.

[038] Add H2O (100 mg, 5.56 mmol) and TMSCl (361 mg, 3.34 mmol) to a solution of 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1] octan -3-ol (877 mg, 3.03 mmol) in 2-butanone (60 mL). Stir the mixture at room temperature for 12 hours. Concentrate the mixture under vacuum to remove 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol hydrochloride as white solid (986 mg, Yield: 100%). 1H NMR (400 MHz, D2O) δ 7.23-7.27 (t, J = 16.4, 1H), 7.00-7.02 (d, J = 8.0, 1H), 6.95 -6.96 (t, J = 4.0, 1H), 6.78-6.80 (d, J = 10.4, 1H), 3.71 (s, 3H), 3.05-3, 19 (m, 1H), 2.52-2.58 (m, 4H), 2.14-2.26 (m, 4H), 2.09-2.14 (m, 2H), 2.05- 2.06 (d, J = 2.4, 1H), 1.89-1.92 (m, 1H), 1.78-1.80 (m, 1H), 1.51-1.68 (m , 4H), 1.40-1.52 (m, 1H).

[039] The following compounds can be prepared essentially by the method of Example 14.

[040] Add TBSCl (3.37 g, 22.37 mmol) and imidazole (1.9 g, 27.96 mmol) to a solution of 3-bromo-4-fluoro-phenol (3.56 g 18.64 mmol) in CH2Cl2 (60 ml). Stir the solution at room temperature for 3 hours. Quench the reaction with water (30 mL). Extract the aqueous layer with CH2Cl2 (30 mL x 3). The combined organic layers are washed with brine, dried over Na2SO4, concentrated in vacuo. The residue is purified by silica gel chromatography (petroleum ether) to remove (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane as colorless oil (5.81 g, 99%), MS ( m/z): 303 (M-1).

Exemplo 39 Síntesede2-dimetilaminometil-3-(2-fluoro-5-hidróxi-fenil)- biciclo[3.2.1]octan -3-ol

[041] The following compounds can be prepared essentially by Preparation method 26.

Example 39 Synthesis of 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol

[042] Cool a solution of (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane (5.81 g, 19.03 mmol) in THF (100 mL) to -78°C under N 2 . Then add dropwise a solution of t-BuLi (14.6 mL, 19.03 mmol) in hexane via syringe to the reaction solution. After being stirred at -78°C for 1 hour, add dropwise a solution of 2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-one (2.87 g, 15.86 mmol) in THF (1, 5 ml) to the reaction mixture and stir the mixture at -78°C for an additional 1 hour. Quench the reaction with 60 mL of dilute HCl (2N), and stir at room temperature for 2 hours. Basify the resulting mixture with K2CO3 to pH = 9, and extract with EtOAc (100 mL X 3). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purify the residue by silica gel chromatography (CH2Cl2 to CH2Cl2:MeOH = 10:1) to give 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol as white solid (2.38 g, yield: 51.2%). MS (m/z): 294 (M+1).

Exemplo 52 Síntesede2-dimetilaminometil-3-(2-fluoro-5-hidróxi-fenil)- biciclo[3.2.1]octan -3-ol

[043] The following compounds can be prepared essentially by the method of Example 39.

Example 52 Synthesis of 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol

[044] Add H2O (175.1 mg, 9.73 mmol) and TMSCl (1.057 g, 9.73 mmol) to a solution of 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicycle [3.2.1]octan-3-ol (2.38 g, 8.11 mmol) in 2-butanone (60 mL). Stir the reaction mixture at room temperature for 3 hours. After removing the solvent by evaporation, wash the residue with EtOAc to remove 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol hydrochloride as white solid (2.23 g, yield: 83.5%). 1H NMR (400 MHz, D2O) δ 6.89-6.93 (m, 2H), 6.66-6.70 (m, 1H), 3.10-3.14 (m, 1H), 2, 59-2.65 (m, 4H), 2.42-2.44 (d, J = 8.0.1H), 2.36-2.41 (d, J = 20.0, 3H), 2 .30-2.33 (d, J = 12.0, 2H), 2.18 (s, 1H), 1.89-1.95 (m, 1H), 1.74-1.78 (m, 1H), 1.51-1.67 (m, 4H), 1.47-1.50 (m, 1H).

Exemplo 65 Síntese de 3-(2-dimetilaminometil-3-hidróxi-biciclo [3.2.1]oct-3-il)-4- fluoro-fenil éster de ácido 2,2-dimetil-propiônico

[045] The following compounds can be prepared essentially by the method of Example 52.

Example 65 Synthesis of 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester of 2,2-dimethyl-propionic acid

[046] Stir a mixture of 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2. 1]octan-3-ol (587 mg, 2.0 mmol), 2,2-dimethyl-propionyl chloride (361.5 mg, 3.0 mmol) and triethyl amine (606 mg, 6.0 mmol) in CH2Cl2 (60 mL) at room temperature for 12 hours. Concentrate the mixture in vacuo, and purify the residue by preparative TLC to remove 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl acid ester 2 ,2-dimethyl-propionic (368 mg, yield: 48.8%). MS (m/z): 378 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.29-7.32 (d, J1 = 6.8, J2 = 2.8, 1H), 7.14-7.19 (d, J1 = 11. 6, J2 = 8.8, 1H), 7.01-7.05 (m, 1H), 3.19-3.25 (m, 1H), 2.64-2.67 (d, J = 13 0.6, 1H), 2.51 (s, 6H), 2.46-2.48 (m, 2H), 2.36-2.40 (m, 2H), 2.25-2.30 (m , 1H), 1.99-2.06 (m, 1H), 1.78-1.85 (m, 4H), 1.61-1.65 (m, 1H), 1.36 (s, 9H ).

Exemplo 71 Síntese de cloridrato de 3-(2-dimetilaminometil-3-hidróxi-biciclo [3.2.1]oct-3-il)-4-fluoro-fenil éster de ácido 2,2-dimetil-propiônico

[047] The following compounds can be prepared essentially by the method of Example 65.

Example 71 Synthesis of 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester of 2,2-dimethyl-propionic acid hydrochloride

[048] Add H2O (9mg, 0.5mmol) and TMSCl (43mg, 0.397mmol) to a solution of 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)- 2-fluoro-phenyl ester of 2,2-dimethyl-propionic acid (150 mg, 0.397 mmol) in 2-butanone (50 mL). Stir the reaction mixture at 0°C for 2 hours. Evaporate the mixture under vacuum to remove 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester of 2,2-dimethyl-propionic acid hydrochloride as white solid (164 mg, yield: 100%). 1H NMR (400 MHz, Methanol-d4) δ 7.30-7.32 (d, J1 = 6.8, J2 = 2.8, 1H), 7.15-7.20 (d, J1 = 11. 6, J2 = 8.8, 1H), 7.03-7.06 (m, 1H), 3.28-3.31 (m, 1H), 2.77-2.81 (m, 4H), 2.37-2.52 (m, 7H), 2.27 (m, 1H), 2.03 (m, 1H), 1.79-1.86 (m, 4H), 1.63-1, 65 (m, 1H), 1.38 (s, 9H).

[049] The following compounds can be prepared essentially by the method of Example 71.

Exemplo 77 Síntese de 3-(4-dimetilaminometil-biciclo[3.2.1 ]oct-2-en-3-il)-fenol

[050] For compounds of Formula Ib, below, Schemes D and E and Examples 77-113 illustrate methods of preparing them.

Example 77 Synthesis of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol

[051] Add TsOH (5.0 g, 29.1 mmol) to a solution of 2-dimethylaminomethyl-3-(3-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol (4.8 g) , 17.5 mmol) in toluene (150 ml). Heat the reaction mixture to reflux for 2 hours and then quench the reaction by adding saturated aqueous K2CO3 (20 mL). Extract the aqueous layer with EtOAc (60 mL x 3). The combined organic layers are washed with brine, dried over Na2SO4 and evaporated under vacuum. Purify the residue by preparative HPLC to yield 3-(4-dimethyl aminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol as a white solid (2.27 g, 50.2%). MS (m/z): 258 (M+1).

Exemplo 91 Síntese de Cloridrato de 3-(4-dimetilaminometil-biciclo[3.2.1]oct-2-en- 3-il)-fenol

[052] The following compounds can be prepared essentially by the method of Example 77.

Example 91 Synthesis of 3-(4-Dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol Hydrochloride

[053] Add H2O (392 mg, 21.8 mmol) and TMSCl (1.4 g, 12.9 mmol) to a solution of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en- 3-yl)-phenol (2.8 g, 10.9 mmol) in 2-butanone (200 mL). Stir the reaction mixture at room temperature for 12 hours. Collect the precipitate by filter, and wash with EtOAc (30 mL x 2), vacuum dried to remove 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl) hydrochloride -phenol as white solid (2.41 g, yield: 75.5%). 1H NMR (400 MHz, D2O) δ 7.20-7.24 (t, J = 15.6, 1H), 6.76-6.81 (m, 2H), 6.72 (s, 1H), 6.15 (d, J = 6.4, 1H), 3.58-3.61 (d, J = 12.8, 1H), 3.08-3.14 (t, J = 26.0, 1H), 2.89-2.92 (m, 1H), 2.88 (s, 3H), 2.76 (s, 3H), 2.56 (m, 1H), 2.45 (m, 1H) ), 1.72-1.83 (m, 6H).

Exemplo 105 Síntese de 3-(4-dimetilaminometil-biciclo[3.2.1]oct- 2-en-3-il)-fenil éster de ácido 2,2-dimetil-propiônico

[054] The following compounds can be prepared essentially by the method of Example 91.

Example 105 Synthesis of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester of 2,2-dimethyl-propionic acid

[055] Stir a mixture of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (200 mg, 0.778 mmol), 2,2-dimethyl-propionyl chloride ( 111mg, 0.927mmol) and triethyl amine (234mg, 2.316mmol) in CH 2 Cl 2 (40ml) at room temperature for 12 hours. Concentrate the mixture in vacuo, and purify the residue by preparative TLC to remove the acid 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester 2,2- dimethyl-propionic as white solid (232 mg, yield: 87.5%). MS (m/z): 342 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.29-7.32 (t, J = 15.6Hz, 1H), 7.06-7.08 (d, J = 7.6, 1H) , 6.886.90 (d, J1 = 8.0, J2 =1.6, 1H), 6.84-6.85 (t, J = 3.6, 1H), 6.05-6.07 (d , J=6.8, 1H), 3.22-3.32 (m, 1H), 2.52-2.60 (m, 1H), 2.62-2.63 (m, 1H), 2 .37-2.41 (m, 1H), 2.17 (s, 6H), 2.07-2.14 (m, 1H), 1.71-1.85 (m, 6H), 1.37 (s, 9H).

Exemplo 111 Síntese de cloridrato de 3-(4-dimetilaminometil-biciclo[3.2.1]oct- 2-en- 3-il)-fenil éster de ácido 2,2-dimetil-propiônico

[056] The following compounds can be prepared essentially by the method of Example 105.

Example 111 Synthesis of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester of 2,2-dimethyl-propionic acid hydrochloride

[057] Add H2O (18mg, 1mmol) and TMSCl (75mg, 0.69mmol) to a solution of 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl) -phenyl ester of 2,2-dimethyl-propionic acid (197 mg, 0.58 mmol) in 2-butanone (70 mL). Stir the reaction mixture at room temperature for 2 hours. Evaporate the mixture under vacuum to furnish 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester of 2,2-dimethyl-propionic acid hydrochloride as a white solid (219 mg, yield: 100%). 1H NMR (400 MHz, Methanol-d4) δ 7.38-7.42 (t, J = 16.4, 1H), 7.13-7.15 (d, J1 = 7.2, J2 = 0, 8.1H), 6.96-6.98 (m, 2H), 6.216.23 (d, J = 6.8, 1H), 3.68-3.71 (d, J = 12.0, 1H ), 3.16-3.23 (t, J = 25.6, 1H), 2.99-3.00 (m, 1H), 2.88-2.92 (d, J = 14.8, 6H), 2.65 (m, 1H), 2.60 (m, 1H), 1.95-1.98 (m, 1H), 1.82-1.86 (m, 5H), 1.37 (s, 9H).

[058] The following compounds can be prepared essentially by the method of Example 111.

[059] For compounds of Formula Ic, below, Schemes F and G and Preparations and/or Examples 114-140 illustrate methods of preparing them.

[060] Add Pd/C (80 mg) to a solution of 3-(4-dimethylamino-methyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (250 mg, 0.97 mmol) ) in MeOH (40 ml). Then stir the mixture at 25°C for 12 hours under 3.16377 kg/cm2 (45 PSI) of H2. After filtration, concentrate the solution under vacuum to give 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol as white solid (252 mg, yield: 100%). MS (m/z): 260 (M+1).

Exemplo 122 Síntese de cloridrato de 3-(2-dimetilaminometil-biciclo[3.2.1]oct-3-il)- Fenol

[061] The following compounds can be prepared essentially by the method of Example 114.

Example 122 Synthesis of 3-(2-Dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-Phenol Hydrochloride

[062] Add H2O (70mg, 3.89mmol) and TMSCl (126mg, 1.17mmol) to a solution of 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol (252 mg, 0.97 mmol) in 2-butanone (30 ml). Then stir the reaction mixture at room temperature for 12 hours. Evaporate the mixture under vacuum to remove 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol hydrochloride as white solid (286 mg, yield: 99.8%), 1H NMR (400 MHz, D2O) δ 7.04-7.07 (t, J = 10.4, 1H), 6.58-6.72 (m, 3H), 2.80-2.91 (m, 1H), 2.52-2.54 (m, 3H), 2.44-2.48 (m, 3H), 2.33-2.41 (m, 1H), 2.20-2.29 (m, 1H) ), 2.11 (s, 1H), 1.99 (s, 2H), 1.36-1.47 (m, 8H).

Exemplo 130 Síntese de 3-(2-dimetilaminometil-biciclo[3.2.1]oct -3-il)-fenil éster de ácido 2,2-dimetil-propiônico

[063] The following compounds can be prepared essentially by the method of Example 122.

Example 130 Synthesis of 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester of 2,2-dimethyl-propionic acid

[064] Stir a mixture of 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol (200 mg, 0.772 mmol), 2,2-dimethyl-propionyl chloride (111.6 mg) , 0.927 mmol) and triethyl amine (234 mg, 2.316 mmol) in CH 2 Cl 2 (40 mL) at room temperature for 12 hours. Concentrate the mixture under reduced pressure, and purify the residue by preparative TLC to give 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester of 2,2-dimethyl-propionic acid as white solid (217 mg, yield: 81.9%). MS (m/z): 344 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.36-7.40 (t, J = 13.6, 1H), 7.19-7.21 (d, J = 7.2, 1H), 7 .03 (s, 1H), 6.92-6.94 (d, J = 8.0, 1H), 2.97-3.03 (t, J = 23.6, 1H), 2.49- 2.68 (m, 6H), 2.40-2.44 (d, J = 13.2, 1H), 2.35 (s, 2H), 2.17-2.21 (m, 2H), 1.60-1.84 (m, 8H), 1.37 (s, 9H).

Exemplo 136 Síntese de cloridrato de 3-(2-dimetilaminometil-biciclo[3.2.1]oct-3-il)- fenil éster de ácido 2,2-dimetil-propiônico

[065] The following compounds are prepared essentially by the method of Example 130.

Example 136 Synthesis of 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester of 2,2-dimethyl-propionic acid hydrochloride

[066] Add H2O (9mg, 0.5mmol) and TMSCl (39mg, 0.357mmol) to a solution of 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl acid ester 2,2-dimethyl-propionic (102 mg, 0.297 mmol) in 2-butanone (50 mL). Then stir reaction mixture at room temperature for 4 hours. Evaporate the mixture under vacuum to remove 2,2-dimethyl-propionic acid 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester hydrochloride as white solid (112 mg, yield: 100%), 1H NMR (400 MHz, Methanol-d4) δ 7.38-7.42 (t, J = 15.6, 1H), 7.20-7.22 (d, J = 7.6, 1H), 7.05 (s, 1H), 6.94-6.96 (m, 1H), 3.08-3.14 (m, 1H), 2.79 (s, 3H), 2.66 (s, 3H), 2.53-2.57 (m, 2H), 2.36 (s, 2H), 2.23 (m, 1H), 1.61-1.85 (m, 8H), 1.39 (s, 9H).

[067] The following compounds can be prepared essentially by the method of Example 135.

[068] For compounds of Formula Id, below, Schemes H-J and Preparations and/or Examples 147-164 illustrate methods of preparing them.

[069] Add trimethylsulfoxonium iodide (126.3 g, 0.572 mol) to a suspension of sodium hydride (22.9 g, 60% in oil dispersion, 0.572 mol) in dry DMSO (550 mL) at room temperature in 10 minutes. Stir the mixture for 1 hour, then add dropwise a solution of cyclohex-2-enone (51.2 g, 0.52 mol) in dry DMSO (100 mL) to the reaction mixture. Stir the reaction mixture at 50°C for an additional 2 hours. Pour the reaction mixture into ice water, and extract the aqueous mixture with CH2Cl2 (300 mL x 3). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo. Purify the residue by distillation (55~60°C, 5 mmHg) to give bicyclo[4.1.0] heptan-2-one as colorless oil (38.45 g, 66.6%), MS (m/z): 109 (M-1).

Preparação 143 Síntese de (biciclo[4.1.0]hept-2-en-2-ilóxi)-trimetil-silano

[070] The following compound can be prepared essentially by Preparation method 141.

Preparation 143 Synthesis of (bicyclo[4.1.0]hept-2-en-2-yloxy)-trimethyl-silane

[071] Add dropwise bicyclo[4.1.0]heptan-2-one (43.3 g, 0.393 mol) in dry THF (50 ml) to a solution of LDA (237 ml, 0.472 mol) in THF (500 mol) mL). Stir the reaction mixture for 30 minutes and then add dropwise TMSCl (64.2 g, 0.59 mol) to the reaction mixture. Stir the resulting solution for an additional 1 hour. Pour the mixture into ice water (92 mL) and extract the aqueous mixture with EtOAc (100 mL x 3). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude (bicyclo[4.1.0]hept-2-en-2-yloxy)-trimethyl-silane (68.0 g, 95.0%) as yellowish oil, MS (m/z): 181 (M-1).

Preparação 145 Síntese de 3-dimetilaminometil-biciclo[4.1.0]heptan-2-ona

[072] The following compound can be prepared essentially by Preparation method 143.

Preparation 145 Synthesis of 3-dimethylaminomethyl-bicyclo[4.1.0]heptan-2-one

[073] Add (bicyclo[4.1.0]hept-2-en-2-yloxy)-trimethyl-silane (72.9 g, 0.40 mol) to a cooled suspension of N,N-dimethylmethyleneiminium chloride (48 0.6 g, 0.52 mol) in CH 2 Cl 2 (400 mL) at 0°C. After being stirred overnight at room temperature, dilute the reaction mixture with 2N HCl (200 mL). After removing organic layers, wash the aqueous layer with EtOAc (50 mL x 3) and then basify with NaOH to PH = 10. Extract the resulting mixture with EtOAc (100 mL x 4). The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purify the residue by distillation (80 ~ 85 °C, 5 mmHg) to give 3-dimethylaminomethyl-bicyclo[4.1.0]heptan-2-one (16.0 g, 24.0%) as colorless oil, MS (m/ z): 168 (M+1).

Exemplo 147 Síntese de 3-Dimetilaminometil-2-(3-hidróxi-fenil)-biciclo[4.1.0]heptan-2-ol

[074] The following compound can be prepared essentially by Preparation method 145.

Example 147 Synthesis of 3-Dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol

[075] Add a solution of t-BuLi (5.8 mL, 8.68 mmol) via syringe to a solution of 3-bromo-phenol (752 mg, 4.34 mmol) in THF (60 mL) at -78°C under N2. After being stirred at -78°C for 1 hour, add a solution of 3-dimethylaminomethyl-bicyclo[4.1.0]heptan-2-one (300 mg, 2.17mmol) in THF (2ml) to the reaction mixture and stir the reaction mixture at -78°C for an additional 2 hours. Quench the reaction mixture with saturated NH4Cl solution (30 mL). Extract the resulting aqueous mixture with EtOAc (60 mL x 3). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purify the residue by preparative HPLC to remove 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol as white solid (73 mg, yield: 12.9%). MS (m/z): 262 (M+1).

Exemplo 153 Síntese de cloridrato de 3-dimetilaminometil-2-(3-hidróxi-fenil)- biciclo[4.1.0] heptan-2-ol

[076] The following compounds can be prepared essentially by the method of Example 147.

Example 153 Synthesis of 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0] heptan-2-ol hydrochloride

[077] Add H2O (10 mg, 0.560 mmol) and TMSCl (33 mg, 0.308 mmol) to a solution of 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0] heptan-2-ol (73 mg, 0.280 mmol) in 2-butanone (10 mL). Then stir the mixture at room temperature for 2 hours. Evaporate the mixture under vacuum to remove 3-dimethylaminomethyl-2-(3-hydroxyl-phenyl)-bicyclo[4.1.0]heptan-2-ol hydrochloride as a white solid (83 mg, yield: 100%). 1H NMR (400 MHz, Methanol 4 ) δ 7.21-7.25 (t, J=16.0, 1H), 7.17-7.18 (t, J=4.4, 1H), 7.11 -7.13 (m, 1H), 6.76-6.79 (d, J= 10.0, 1H), 3.23-3.25 (m, 1H), 2.68-2.69 ( m, 7H), 2.14-2.17 (m, 1H), 2.04-2.09 (m, 1H), 1.76-1.81 (m, 1H), 1.62-1, 64 (m, 1H), 1.47-1.49 (m, 1H), 1.11-1.16 (m, 1H), 0.93-1.05 (m, 1H), 0.73- 0.84 (m, 1H), 0.50-0.53 (m, 1H).

Exemplo 157 Síntese de 3-dimetilaminometil-2-(3-fluoro-5-hidróxi-fenil)-biciclo[4.1.0] heptan-2-ol

[078] The following compounds can be prepared essentially by the method of Example 153.

Example 157 Synthesis of 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0] heptan-2-ol

[079] Add a solution of t-BuLi (19.4 mL, 25.2 mmol) via syringe to a solution of (3-bromo-5-fluoro-phenoxy)-tert-butyl-dimethyl-silane ( 6.99 g, 22.9 mmol) in THF (100 mL) at -78°C under N 2 . After being stirred at -78°C for 1 hour, add a solution of 3-dimethylaminomethyl-bicyclo[4.1.0]heptan-2-one (2.55 g, 15.3 mmol) dropwise to the reaction mixture. and stir the reaction mixture at -78°C for an additional 2 hours. Quench the reaction with saturated NH4Cl solution (30 mL). Extract the resulting aqueous mixture with EtOAc (100 mL x 3). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Treat the residue with TBAF (6.00 g, 22.9 mmol) in CH 2 Cl 2 (80 mL) at room temperature for 4 hours. Concentrate the mixture, and purify the residue by preparative HPLC to remove 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol as white solid (592 mg, yield : 13.9%). MS (m/z): 280 (M+1).

Exemplo 160 Síntese de cloridrato de 3-dimetilaminometil-2-(3-fluoro-5-hidróxi-fenil)- biciclo [4.1.0] heptan-2-ol

[080] The following compounds can be prepared essentially by the method of Example 157.

Example 160 Synthesis of 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0] heptan-2-ol hydrochloride

[081] Add H2O (18 mg, 1.0 mmol) and TMSCl (92 mg, 0.857 mmol) to a solution of 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0 ]heptan-2-ol (218 mg, 0.781 mmol) in 2-butanone (70 mL). Then stir the reaction mixture at room temperature for 2 hours. After removing the solvent by evaporation, wash the residue with EtOAc (3 mL x 2) to remove 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-hydrochloride 2-ol as white solid (72 mg, yield: 67.8%). 1H NMR (400 MHz, D2O) δ 6.93 (s, 1H), 6.87-6.89 (d, J = 9.6, 1H), 6.42-6.58 (m, 1H), 3.323.33 (t, J = 3.2, 1H), 2.98-3.04 (m, 1H), 2.77 (m, 6H), 2.22-2.23 (m, 1H), 2.06 (m, 1H), 1.81-1.85 (m, 2H), 1.61-1.71 (m, 1H), 1.17-1.21 (m, 1H), 1, 08-1.10 (m, 1H), 0.83-0.86 (m, 1H), 0.56-0.60 (m, 1H).

Exemplo 163 Síntese de 3-(3-dimetilaminometil-2-hidróxi-biciclo [4.1.0]hept-2-il)-5- fluoro-fenil éster de ácido 2,2-dimetil-propiônico

[082] The following compounds can be prepared essentially by the method of Example 160.

Example 163 Synthesis of 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-5-fluoro-phenyl ester of 2,2-dimethyl-propionic acid

[083] Stir a mixture of 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo [4. 1.0]heptan-2-ol (295 mg, 1.06 mmol), 2,2-dimethyl-propionyl chloride (153 mg, 1.27 mmol) and triethylamine (321 mg, 3.18 mmol) in CH2Cl2 (40 mL) at room temperature for 5 hours. Quench the mixture with 10 mL of H2O. Separate the aqueous layer, and concentrate the organic layer under reduced pressure. Purify the residue by preparative TLC to remove 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-5-fluoro-phenyl ester of 2,2-dimethyl-propionic acid as white solid (228 mg, yield: 59.2%). MS (m/z): 364 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.25-7.28 (d, J1 = 10.4, J2 = 1.6, 1H), 7.14 (s, 1H), 6.76-6 .78 (d, J1 = 9.2, J2 = 2.4, 1H), 2.37-2.46 (m, 1H), 2.15-2.19 (m, 7H), 1.99- 2.03 (d, J = 13.2, 1H), 1.82 (m, 2H), 1.53-1.68 (m, 2H), 1.37 (s, 9H), 1.17 ( m, 1H), 1.01-1.06 (m, 1H), 0.75-0.81 (m, 1H), 0.48-0.50 (m, 1H).

[084] The following compound can be prepared essentially by the method of Example 163.

Preparação 165 (1R,2R,5S)-2,6,6-trimetilbiciclo[3.1.1]heptan-3-ona

[085] For compounds of Formula Ie, below, Scheme K and Preparations and/or Examples 165-176 illustrate methods of preparing them.

Preparation 165 (1R,2R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one

[086] Jones Reagent: Add a mixture of 9 ml of H2SO4 and 40 ml of H2O to a solution of Cr2O3 (15.0 g, 0.15 mol) in H2O (20 mL) at 0°C.

[087] Add dropwise the above Jones reagent to a solution of (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ol (23.1 g, 0, 15 mol) in acetone (100 ml) over a period of 2 hours at 0°C. Stir the resulting mixture for an additional 1 hour. Dilute the mixture with 100 mL of water and then extract the aqueous mixture with ether (50 mL X3). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to remove (1R,2R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan- crude 3-one as pale yellow oil (21.3 g, yield: 93.4%), MS (m/z): 151 (M-1).

Preparação 167 (1 R,2R,4S,5S)-2,6,6-trimetil-4- ((metil(fenetil)amino)metil)biciclo[3.1. 1 ]heptan-3-ona

[088] The following compound can be prepared essentially by Preparation method 165.

Preparation 167 (1R,2R,4S,5S)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1. 1]heptan-3-one

[089] Stir a mixture of (1R,2R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one (7.6 g, 50.0 mmol), (HCHO)n (1 0.8 g, 60.0 mmol), N-methyl-2-phenylethanamine (6.75 g, 50.0 mmol) and 5.0 mL of concentrated HCl in MeCN (50 mL) at 70°C for 3 hours. After removing the solvent in vacuo, dissolve the residue in H2O (30 mL) and wash with EtOAc (20 mL X 2). Basify the aqueous solution with K2CO3 to pH = 9 and extract the resulting mixture with EtOAc (30 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to remove the crude product as a brown oil, which was also purified by silica gel chromatography to remove (1R,2R ,4S,5S)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-one as pale yellow oil (9.24 g, yield: 61 .8%), MS (m/z): 300 (M+1).

Exemplo 169 (1R,2R,3S,4S,5S)-3-(3-hidroxifenil)-2,6,6-trimetil-4- ((metil(fenetil)amino)metil) biciclo[3.1. 1 ]heptan-3-ol

[090] The following compound can be prepared essentially by Preparation method 167.

Example 169 (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1. 1]heptan-3-ol

[091] Add a solution of t-BuLi (20 mL, 26.0 mmol) via syringe to a solution of 3-bromo-phenol (2.06 g, 12 mmol) in THF (20 mL) a - 78oC under N2. After being stirred at -78°C for 1 hour, add a solution of (1R,2R,4S,5S)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1. 1]heptan-3-one (2.99 g, 10 mmol) in THF (2 mL) to the reaction mixture and stir the reaction mixture at -78°C for an additional 2 hours. Quench the reaction with saturated NH4Cl solution (30 mL). Extract the aqueous mixture with EtOAc (60 mL x 3). The combined organic layers are washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purify the residue by preparative HPLC to remove (1R,2R,3S,4S, 5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[ 3.1.1] heptan-3-ol as a pale yellow oil (0.27 g, yield: 6.9%), MS (m/z): 394 (M+1).

Exemplo 173 Cloridrato de (1 R,2R,3S,4S,5S)-3-(3-hidroxifenil)-2,6,6-trimetil-4- ((metil(fenetil)amino)metil)biciclo[3.1. 1 ]heptan-3-ol

[092] The following compound can be prepared essentially by the method of Example 169.

Example 173 (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1. 1]heptan-3-ol

[093] Add H2O (4 mg, 0.25 mmol) and TMSCl (27 mg, 0.25 mmol) to a solution of (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2 ,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol (100 mg, 0.25 mmol) in 2-butanone (5 mL). Stir the reaction mixture at room temperature for 3 hours. After removing the solvent by evaporation, wash the residue with EtOAc (1 mL X 2) and dry under vacuum to remove the hydrochloride of (1R,2R, 3S,4S,5S)-3-(3-hydroxyphenyl)-2, 6.6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3-ol (93 mg, yield: 85.3%) as white solid. 1H NMR (400 MHz, D2O) δ 7.21-7.32 (m, 7H), 7.97-7.99 (d, J = 7.2, 1H), 6.71-6.78 (dd , J1 = 8.0, J2 = 22.0, 1H), 2.86-3.33 (m, 5H), 2.43-2.68 (m, 7H), 2.11-2.20 ( m, 2H), 1.73-1.75 (m, 1H), 1.23-1.25 (d, J = 5.6, 3H), 1.04-1.05 (d, J = 4 0.4, 3H), 0.69-0.71 (d, J = 5.6.3H). [α]20,D = -8.6 (c=1.4 mg/ml, MeOH).

[094] The following compounds can be prepared essentially by the method of Example 173.

[095] For compounds of Formula If, below, Scheme L and Preparations and/or Examples 177-180 illustrate methods of preparing them.

[096] Add dropwise hexahydro-1H-inden-4(2H)-one (1.6 g, 11.6 mmol) in dry THF (5 mL) to a solution of LDA (23.2 mL, 23.2 mmol) in THF (30 mL). Stir the reaction mixture for 30 minutes and then add dropwise TMSCl (3.5 g, 32.0 mmol) to the reaction mixture. Stir the resulting solution for an additional 1 hour. Pour the mixture into ice water (50 mL) and extract the aqueous mixture with EtOAc (50 mL x 3). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give crude (2,3,3a,6,7,7a-hexahydro-1H-inden-4-yloxy)trimethylsilane (2. .45 g, 100%) as yellowish oil, MS (m/z): 209 (M-1). Preparation 178 5-((dimethylamino)methyl)hexahydro-1H-inden-4(2H)-one

[097] Add (2,3,3a,6,7,7a-hexahydro-1H-inden-4-yloxy)trimethylsilane (2.45 g, 11.6 mmol) to a cooled suspension of iodide iodide. N,N-dimethylmethyleneiminium (2.78 g, 15.0 mmol) in CH 2 Cl 2 (60 mL) at 0°C. After being stirred overnight at room temperature, dilute the reaction mixture with 2N HCl (20 mL). After removing the organic layers, wash the aqueous layer with EtOAc (30 mL x 3) and then basify with NaOH to PH = 10. Extract the resulting mixture with EtOAc (50 mL x 4). The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 5-((dimethylamino)methyl)hexahydro-1H-inden-4(2H)-one (623 mg, 27.5% ) as oil, MS (m/z): 196 (M+1). Example 179 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol

[098] Add a solution of t-BuLi (2.1 mL, 3.07 mmol) via syringe to a solution of 3-bromo-phenol (569 mg, 3.076 mmol) in THF (50 mL) a - 78oC under N2. After being stirred at -78°C for 1 hour, add a solution of 35-((dimethylamino)methyl)hexahydro-1H-inden-4(2H)-one (300 mg, 1.54 mmol) in THF ( 2 ml) to the reaction mixture and stir the reaction mixture at -78°C for an additional 2 hours. Quench the reaction mixture with saturated NH4Cl solution (30 mL). Extract the resulting aqueous mixture with EtOAc (50 mL x 3). The combined organic layers are washed with brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purify the residue by preparative HPLC to remove 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol (92 mg, yield: 19.7%). MS (m/z): 290 (M+1). Example 180 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol hydrochloride

[099] Add H2O (10 mg, 0.54 mmol) and TMSCl (35 mg, 0.33 mmol) to a solution of 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H -inden-4-ol (78 mg, 0.27 mmol) in 2-butanone (10 mL). Then stir the mixture at room temperature for 12 hours. Evaporate the mixture under vacuum to remove 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol hydrochloride as a mixture of 4 diastereoisomers (91 mg, yield: 100 %). Example 181 (+)-(1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1] octan-3-ol and (-)-( 1R,2S,3S,5S)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol.

CI1[0100] Separate 0.5 g of 2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1] octan-3-ol (1.82 mmol) by SFC to give (+)- (1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol (8 mg, yield: 3.2%; MS ( m/z): 276 (M+1)) and (-)-(1R,2S,3S,5S)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan -3-ol (135 mg, yield: 54.0%; MS (m/z): 276 (M+1)) as white solids. The relative configuration of the two enantioisomers is confirmed by 2D NMR and the absolute configuration of the two enantioisomers is determined by X-ray analysis. The (+)-Enantioisomers below exhibit better biological activity than (-)-enantioisomer in bioassay(s). Example 182 (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochloride

CI1

[0101] Stir a solution of (S)-2-phenylpropanoic acid (300 mg, 2.0 mmol) in 5 mL of oxalyl chloride for 3 hours at room temperature. After removing the solvent under vacuum, (S)-2-phenylpropanoyl chloride is obtained as pale yellow oil. Dissolve the oil in 10 mL of CH2Cl2. Add (1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol (400mg, 1.45mmol) and Et3N( 293 mg, 2.9 mmol) to the solution. Stir the resulting mixture at room temperature for an additional 3 hours. After adding 20 mL of water, basify the mixture with K2CO3 to pH = 10, and extract the aqueous mixture with EtOAc (20 mL X 3). The combined organic layers are washed with brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purify the residue by silica gel chromatography (CH2Cl2:MeOH = 30:1) to give (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3 2-phenylpropanoate -hydroxybicyclo[3.2.1]octan-3-yl)phenyl (500 mg, 84.7%; MS (m/z): 408 (M+1)) as yellow oil. Stir (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate ( 250 mg, 0.61 mmol) with H 2 O (11 mg, 0.61 mmol) and TMSCl (66 mg, 0.61 mmol) in 2-butanone (5 mL) for 3 hours. Collect the precipitate by filtration to furnish (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan- 2-phenylpropanoate hydrochloride 3-yl)phenyl (215 mg, yield: 79.3%) as white solid. The absolute configuration of its hydrochloride salt form was confirmed by X-ray analysis. 1H NMR (400 MHz, DMSO) δ 9.81 (br, 1H), 7.31-7.41 (m, 7H), 7 .14 (s, 1H), 6.87-6.90 (m, 1H), 5.01 (s, 1H), 4.08-4.10 (m, 1H), 3.02-3.08 (m, 1H), 2.42-2.58 (m, 4H), 2.12-2.26 (m, 6H), 1.90-1.99 (m, 2H), 1.75-1 .80 (m, 2H), 1.51-1.59 (m, 6H).

Exemplo 184 3-(4-dimetilaminometil-biciclo[3.2.1 ]oct-2-en-3-il)-fenol e 3-((1 S,5R)-2-((dimetilamino)metil)biciclo[3.2.1 ]oct-2-en-3-il)fenol

[0102] The following compound can be prepared essentially by the method of Example 182.

Example 184 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol and 3-((1S,5R)-2-((dimethylamino)methyl)bicyclo[3.2. 1]oct-2-en-3-yl)phenol

[0103] Add TsOH (5.0 g, 29.1 mmol) to a solution of 2-dimethylaminomethyl-3-(3-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol (4.8 g) , 17.5 mmol) in toluene (150 ml). Heat the reaction mixture to reflux for 2 hours and then quench the reaction by adding saturated aqueous K2CO3 (20 mL). Extract the aqueous layer with EtO-Ac (60 mL x 3). The combined organic layers are washed with brine, dried over Na2SO4 and evaporated under vacuum. Purify the residue by preparative HPLC to yield 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol (2.27 g, 50.2%; MS (m/z) : 258 (M+1)) and 3-(2-((dimethylamino)methyl)bicyclo[3.2.1]oct-2-en-3-yl)phenol (517 mg, 11.5%; MS (m/ z): 258 (M+1)) as a white solid. Two isomers exhibit comparable biological activity in bioassay.

[0104] For compounds of Formula Ig, below, Scheme M and Preparations and/or Examples 185-187 illustrate methods of preparing them.

[0105] Stir a mixture of spiro[2.5]octan-6-one (252 mg, 2.03 mmol), (HCHO)n (61 mg, 2.03 mmol), dimethylamine hydrochloride (166 mg, 2.03 mmol) and 0.3 mL of concentrated HCl in MeCN (30 mL) at 60°C for 6 hours. Quench the reaction with saturated aqueous NH4Cl solution (15 mL). Basify the aqueous solution with K2CO3 to pH = 9. Extract the aqueous mixture with EtOAc (30 mL x 2). The combined organic layers are washed with brine (15 ml), dried over Na2SO4, filtered and concentrated in vacuo. Purify the residue by silica gel chromatography (CH2Cl2:MeOH = 30:1) to give 5-Dimethylaminomethyl-spiro[2.5]octan-6-one as brown oil (142 mg, yield: 38.4%). MS (m/z): 182 (M+1). Example 186 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol

[0106] Cool a solution of (3-bromo-4-fluoro-phenoxy)-tert-butyl-dimethyl-silane (472 mg, 1.547 mmol) in THF (40 mL) to -78°C under N 2 . Then add dropwise a solution of n-BuLi (0.63 mL, 1.547 mmol) in hexane via syringe to the reaction solution. After being stirred at -78°C for 2 hours, add a solution of 5-Dimethylaminomethyl-spiro[2.5]octan-6-one (70 mg, 0.387 mmol) in THF (1 mL) dropwise to the reaction mixture and stir the mixture at -78°C for an additional 2 hours. Quench the reaction with 20 mL of dilute HCl (2N), and stir at room temperature for 2 hours. Basify the resulting mixture with K 2 CO 3 to pH = 9, and extract with EtOAc (30 mL X 2). The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purify the residue by silica gel chromatography (CH2Cl2 to CH2Cl2:MeOH = 10:1) to give 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol as a solid white (41mg, yield: 36.3%). MS (m/z): 294 (M+1). Example 187 5-Dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol hydrochloride

[0107] Add H2O (9 mg, 0.500 mmol) and TMSCl (18 mg, 0.167 mmol) to a solution of 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5] octan-6 -ol (41 mg, 0.139 mmol) in 2-butanone (30 mL). Stir the mixture at 0°C for 2 hours. Concentrate the mixture under vacuum to remove 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol hydrochloride as white solid (46 mg, yield: 100%). 1H NMR (400 MHz, D2O) δ 7.13-7.15 (d, J1 = 6.8, J2 = 3.2, 1H), 6.93-6.98 (d, J1 = 12.0, J2 = 8.8, 1H), 6.69-6.73 (m, 1H), 3.05-3.10 (m, 1H), 2.65-2.76 (m, 8H), 2, 44-2.45 (m, 1H), 2.27-2.35 (m, 2H), 1.70-1.74 (m, 1H), 0.96-0.98 (m, 1H), 0.79-0.82 (m, 1H), 0.45 (m, 1H).

[0108] Mu opioid agonists, such as morpholine, are well known to control pain (Tschenkte et al(s), Tapentadol Hydrochloride - Analgesic, Mu-opioid receptor agonist, Noradrenaline reuptake inhibitor. E. Drugs Fut 2006, 31( 12): 1053). However, mu opioid agonists can also cause various unwanted side effects such as nausea, emesis, constipation, mental confusion, and respiratory depression. Furthermore, the use of opioids for an extended period of time (as needed in chronic pain) can result in physical dependence and addiction.

[0109] Tramadol, a mu opioid agonist, was not associated with clinically significant side effects such as respiratory depression, constipation, or sedation (Id.). Furthermore, the extended use of Tramadol does not result in tolerance, dependence, and addiction (Id.). Tramadol is believed to exert its chronic pain relief through a combination of three mechanisms of action; mu opioid agonism and the inhibition of serotonin and norepinephrine reuptake (Raffa et al., Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic.) J Pharmacol Exp Ther. 1992 Jan; 260(1):275-85). Because Tramadol relieves pain through a combination of mechanisms of action it is able to alleviate pain even though it is a much less potent mu opioid receptor agonist compared to morpholine. The reason for the better side effect profile of Tramadol when compared to morpholine is believed to be a result of lower affinity of Tramadol for the mu opioid receptor. A molecule that, like Tramadol, controls chronic pain by multiple mechanisms of action is desired, and a compound that has a favorable side effect profile, particularly when compared to morpholine, and that also has action for a longer time was desired. Preferably, a molecule that needs to be administered more than once a day for prolonged pain relief is desired.

[0110] Molecules that are mu opioid agonists as well as norepinephrine and/or serotonin reuptake inhibitors are preferably selected for evaluation in the rat tail flick model. In order to be selected for the rat tail flick model the compound needs to demonstrate an EC50 of less than 50 micromolar in a functional assay for mu opioid receptor activation. Furthermore, the active species needs to demonstrate an IC50 of less than 500 micromolar in a functional assay for the inhibition of norepinephrine and/or serotonin reuptake. The activity of the corresponding phenols is used to select the ester and ether prodrugs for evaluation in the rat tail flick model.

[0111] The tail flick test, based on the methods of D'Amour & Smith (J. Pharmacol. Exp. Therap., 72: 74-79, 1941), is used to measure loss of pain sensation in the rat's tail, letting the experimenter evaluate the drugs for the analgesic effect. Afterwards, the method was used in several publications. For example, it was used to evaluate the analgesic effect of O-alkyl tramadol derivatives by Liming Shao and Michael Hewitt etc. (Boiorganic & Medicinal Chemistry Letters, 18:1674-1680, 2008).

[0112] A tail flick unit is employed to measure the latency of the tail flick in response to heat. The unit consists of an infrared (I.R.) source (50W bulb) with adjustable intensity that is focused via a jet on the window mounted on the unit's top panel and on the mouse tail. Since the source of I.R. is focused on the mouse's tail and turned on, a timer starts. When the thermal threshold for pain is reached and the rat flaps its tail, the I.R source automatically turns off and the timer stops, displaying the lag time.

[0113] On the day of the experiment, the animals are tested to determine the reference latency. Each rat is given a test to determine the latency to flick the tail with a 10 second cut-off. Parameters are recorded and those animals within a reference latency of 2-5 seconds are employed in the experiment. Animals are divided into several groups according to reference latency. Tail flick latencies are measured at different time points for up to 180 minutes after administration of vehicle or test articles. If the treatment group continues to exhibit pain control after 180 minutes, additional assessments are taken every 60 minutes until pain control is no longer observed.

[0114] The source of R.R. is set at 40 units (set to elicit the tail flick response in the desired 2-5 seconds in naive animals). A 10-second time cut is fixed to prevent tissue damage in the event that the animal does not flap its tail.

[0115] Vehicle or test articles are administered by intravenous (IV) injection via the tail vein or by oral gavage at time 0. Animals are gently restrained and held on top of a tail flick unit. The tail is then wiped clean with a cotton pad and placed over the I.R. so that the light beam is focused at approximately the middle of the tail's length. After the mouse is in position, the source of I.R. is turned on. When the thermal threshold for pain is reached, the rat taps its tail and the source of I.R. automatically turns off. The latency time (in seconds) is then recorded.

[0116] Data is logged and graphed as %MPE (Maximum Possible Effect). % MPE is calculated using the following Formula: % MPE = [(test latency - reference latency) / (cut-off latency (10 sec.'s) - reference latency)] *100

[0117] Compounds were routinely administered IV in 20% 2-hydroxypropyl-beta-cyclodextrin (20% HP-α-CD). The test article dose levels were 2.5, 5, or 20 mg/kg. Examples 2, 3, 13, 40, 77, 78, 114, and Tramadol provided at least 50% MPE at 20 mg/kg. Compounds 5, 8, 17, 105, 107, 148, 158, and 159 provided at least 50% MPE at 5 mg/kg. Compounds 82, 84, and 116 provided at least 50% MPE at 2.5 mg/kg.

[0118] Compounds were administered by oral gavage in 0.5% methylcellulose at 20 or 30 mg/kg. Examples 2, 3, 13, 115, and Tramadol provided at least 50% MPE at 30 mg/kg. Compounds 5, 39, 65, 106, and 115 provided at least 50% MPE at 20 mg/kg.

[0119] The above data support the claim that the compounds are useful in pain control.

Claims (14)

1. Compound, or salt thereof, characterized by the fact that it has Formula I:

at equal A and selected from:

R1 is hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 alkanol, -(C1-C5 alkyl)phenyl, or phenyl, or a group of the Formula -C(O)-R12, where R12 is C1-C5 alkyl, C1-C5 alkoxy, C1-C5 haloalkyl, C1-C5 alkanol, -(C1-C5 alkyl)phenyl, or phenyl; R2is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, C1-C5haloalkyl, or C1-C5 haloalkoxy; R3is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, halogen, C1-C5haloalkyl, or C1-C5 haloalkoxy; R4is hydrogen, C1-C5 alkyl, or -(C1-C5 alkyl)phenyl; R5is hydrogen, C1-C5 alkyl, or -(C1-C5 alkyl)phenyl; and R11 is hydrogen or C1-C5 alkyl. 2. Compound according to claim 1, characterized in that it is: 2-dimethylaminomethyl-3-(3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(3-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(5-methoxy-2-trifluoromethoxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(2-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(4-fluoro-3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(2-fluoro-3-methoxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(3-methoxy-5-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol; 3-(2-chloro-5-methoxy-phenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol; 3-(3-chloro-5-methoxy-phenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(5-methoxy-2-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(3-methoxy-4-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(3-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(3-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(3-hydroxy-5-trifluoromethyl-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(5-hydroxy-2-trifluoromethoxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(3-hydroxy-4-trifluoromethyl-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(4-fluoro-3-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(2-fluoro-3-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(3-hydroxy-5-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol; 3-(2-chloro-5-hydroxy-phenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol; 3-(3-chloro-5-hydroxy-phenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(5-hydroxy-2-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(3-hydroxy-4-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol; 3-(3,4-difluoro-5-hydroxy-phenyl)-2-dimethylaminomethyl-bicyclo[3.2.1]octan-3-ol; 2-dimethylaminomethyl-3-(2-fluoro-5-hydroxy-phenyl)-bicyclo[3.2.1]octan-3-ol; 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester of 2,2-dimethyl-propionic acid; 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl benzoic acid ester; 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-phenyl ester of 2,2-dimethyl-propionic acid; 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-phenyl benzoic acid ester; 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenyl ester of 2,2-dimethyl-propionic acid; or 3-(2-dimethylaminomethyl-3-hydroxy-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenyl benzoic acid ester; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol; [3-(3-methoxy-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine; [3-(5-methoxy-2-trifluoromethoxy-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-trifluoromethoxy-phenol; [3-(3-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-phenol; [3-(2-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-fluoro-phenol; [3-(3-methoxy-5-methyl-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-5-methyl-phenol; 3-chloro-5-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol; [3-(5-methoxy-2-methyl-phenyl)-bicyclo[3.2.1]oct-3-en-2-ylmethyl]-dimethyl-amine; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-methyl-phenol; 4-chloro-3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl ester of 2,2-dimethyl-propionic acid; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenyl benzoic acid ester; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-phenyl ester of 2,2-dimethyl-propionic acid; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-phenyl ester of isobutyric acid; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-fluoro-phenyl ester of 2,2-dimethyl-propionic acid; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-4-fluoro-phenyl ester of isobutyric acid; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol; [3-(3-methoxy-phenyl)-bicyclo[3.2.1]oct-2-ylmethyl]-dimethyl-amine; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenol; [3-(3-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]oct-2-ylmethyl]-dimethyl-amine; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenol; [3-(2-fluoro-5-methoxy-phenyl)-bicyclo[3.2.1]oct-2-ylmethyl]-dimethyl-amine; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-5-methyl-phenol; [3-(3-methoxy-5-methyl-phenyl)-bicyclo[3.2.1]oct-2-ylmethyl]-dimethyl-amine; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl ester of 2,2-dimethyl-propionic acid; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenyl benzoic acid ester; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenyl ester of 2,2-dimethyl-propionic acid; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-5-fluoro-phenyl ester of isobutyric acid; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester of 2,2-dimethyl-propionic acid; 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-4-fluoro-phenyl ester of isobutyric acid; 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol; 3-dimethylaminomethyl-2-(3-methoxy-phenyl)-bicyclo[4.1.0]heptan-2-ol; 3-dimethylaminomethyl-2-(3-fluoro-5-methoxy-phenyl)-bicyclo[4.1.0]heptan-2-ol; 3-dimethylaminomethyl-2-(5-methoxy-2-methyl-phenyl)-bicyclo[4.1.0]heptan-2-ol; 3-dimethylaminomethyl-2-(3-methoxy-phenyl)-5,5-dimethyl-bicyclo[4.1.0]heptan-2-ol; 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-5,5-dimethyl-bicyclo[4.1.0]heptan-2-ol; 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0] heptan-2-ol; 3-dimethylaminomethyl-2-(2-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol; 3-dimethylaminomethyl-2-(3-hydroxy-5-methyl-phenyl)-bicyclo[4.1.0]heptan-2-ol; 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-5-fluoro-phenyl ester of 2,2-dimethyl-propionic acid; 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-4-fluoro-phenyl ester of 2,2-dimethyl-propionic acid; (1R,2R,3S,4S,5S)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3- hello; (1R,2R,3S,4S,5S)-3-(3-methoxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3- hello; (1S,2S,3R,4R,5R)-3-(3-hydroxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3- hello; (1S,2S,3R,4R,5R)-3-(3-methoxyphenyl)-2,6,6-trimethyl-4-((methyl(phenethyl)amino)methyl)bicyclo[3.1.1]heptan-3- hello; 5-((dimethylamino)methyl)-4-(3-hydroxyphenyl)octahydro-1H-inden-4-ol; (+)-(1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol; (-)-(1R,2S,3S,5S)-2-((dimethylamino)methyl)-3-(3-hydroxyphenyl)bicyclo[3.2.1]octan-3-ol; (S)-3-((1S,2R,3R,5R)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochloride; (S)-3-((1R,2S,3S,5S)-2-((dimethylamino)methyl)-3-hydroxybicyclo[3.2.1]octan-3-yl)phenyl 2-phenylpropanoate hydrochloride; 3-(4-dimethylaminomethyl-bicyclo[3.2.1]oct-2-en-3-yl)-phenol; or 3-((1S,5R)-2-((dimethylamino)methyl)bicyclo[3.2.1]oct-2-en-3-yl)phenol; or such a salt. 3. Compound according to claim 1, characterized in that it is 5-dimethylaminomethyl-6-(2-fluoro-5-hydroxy-phenyl)-spiro[2.5]octan-6-ol, or a salt thereof. 4. Compound according to claim 1, characterized in that it is 2-dimethylaminomethyl-3-(3-methoxy-5-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol, or a salt of this. 5. Compound according to claim 1, characterized in that it is 2-dimethylaminomethyl-3-(3-hydroxy-5-methyl-phenyl)-bicyclo[3.2.1]octan-3-ol, or a salt of this. 6. Compound according to claim 1, characterized in that it is 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol, or a salt of this. 7. Compound according to claim 1, characterized in that it is 3-dimethylaminomethyl-2-(2-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol, or a salt of this. 8. Compound according to claim 1, characterized in that it is 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-5-fluoro-phenyl ester of acid 2 ,2-dimethyl-propionic, or a salt thereof. 9. Compound according to claim 1, characterized in that it is 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-4-fluoro-phenyl ester of acid 2 ,2-dimethyl-propionic, or a salt thereof. 10. A compound, characterized in that it is: 3-dimethylaminomethyl-2-(3-methoxy-phenyl)-5,5-dimethyl-bicyclo[4.1.0]heptan-2-ol; or 3-dimethylaminomethyl-2-(3-hydroxy-phenyl)-5,5-dimethyl-bicyclo[4.1.0]heptan-2-ol, or a salt thereof. 11. Pharmaceutical formulation, characterized in that it comprises a compound, as defined in any one of claims 1 to 10, and one or more pharmaceutically acceptable carriers. 12. Compound or salt, according to any one of claims 1 to 10, characterized in that it is for use in therapy. 13. Compound or salt according to any one of claims 1 to 10, characterized in that it is for use in pain control in a non-human mammal. 14. Compound or salt, according to claim 13, characterized in that said mammal is a dog, rabbit, cat or other domestic animal.